In the human beta globin locus, two sequences (one co-localizing to the initiation site and the other distal to it) are essential for initiating DNA replication. The beta globin initiation site acts as a genetic replicator and is the subject of a detailed structure-function analysis of the sequences required for initiation of DNA. During the last year we have narrowed down the sequences essential for initiation of DNA replication by analyzing several deletion mutants and are now modifying individual sequence elements that are common to replication origins to determine whether these sequences are required for initiation. We are also using the beta-globin locus as a model system to study how replication timing and origin usage are coordinated with gene expression patterns and correlated with local chromatin features. Finally, we are currently developing protocols for genomic hybridization on microarrays, a whole genome approaches to identify multiple replication origins.